Article

"Smoking' mephedrone: The identification of the pyrolysis products of 4-methylmethcathinone hydrochloride

Authors:
  • TU Dublin Tallaght ( Retired from Forensic Science Ireland, Dublin.
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Abstract

The ring-substituted cathinone - mephedrone - has gained popularity among recreational drug users over the past several years. It is generally consumed orally or by snorting but reports indicate that it is also ingested by vaporization/inhalation. This study examines the pyrolysis products produced by heating mephedrone under using simulated 'meth pipe' conditions. Thirteen pyrolysis products were identified, the major ones being iso-mephedrone, 4-methylpropiophenone, 4-methylphenylacetone, two pyrazine derivatives formed by dimerization of mephedrone, N-methylated mephedrone (N,N,4-trimethylcatinone), two hydroxylated oxidation products and a diketone. Other minor products formed were identified as 4-methylacetophenone, two α-chloro ketones and N-methylated iso-mephedrone. Copyright © 2012 John Wiley & Sons, Ltd.

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... 1-(4-Bromo-2,5-dimethoxyphenyl)-2-chloroethanone (9) This was prepared via the sulfuryl chloride method previously reported for 2-chloro-1-(4-methylphenyl)propanone [16] to afford yellow crystals with a 36% yield: m.pt. 116-118°C; 1 5-(4-Bromo-2,5-dimethoxyphenyl)oxazole (10) A mixture of 2-amino-1-(4-bromo-2,5-dimethoxyphenyl)ethanone hydrobromide (177 mg, 0.5 mmol), p-toluenesulfonic acid (5 mg) and triethyl orthoformate (2 mL) was heated at 140°C for 3 h. ...
... The mechanism might have been similar to the formation of iso-mephedrone observed during mephedrone pyrolysis, with the formation of a cyclic amine intermediate that would result in the formation of an iso-2C-B intermediate, followed by deamination. [16] The peak eluting at The fragmentation pattern representing the peak at 7.38 min was initially thought to represent 4-bromo-2,5-dimethoxybenzaldehyde but this was not confirmed when compared to a standard. Instead, an alternative structure was proposed, 1-(4bromo-2-hydroxy-5-methoxyphenyl)ethanone (4), which was confirmed by comparison with a standard and by NMR provided in the Supporting Information. ...
... 1-(4-Bromo-2,5-dimethoxyphenyl)ethanone was formed by loss of the amine group, also seen in the pyrolysis of mephedrone. [16] In mephedrone, however, halogen substitution similar to 1-(4bromo-2,5-dimethoxyphenyl)-2-chloro-ethanone (9) or 2-bromo-1-(4-bromo-2,5-dimethoxyphenyl)-ethanone (11) was not detected. In the later example, chlorination rather than bromination would occur in the case of mephedrone. ...
Article
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2-Amino-1-(4-bromo-2,5-dimethoxyphenyl)ethanone hydrochloride (bk-2C-B) has recently emerged as a new psychoactive substance (NPS). It is most commonly consumed orally although there are indications that it might also be ingested by inhalation or 'smoking'. Information about the stability of bk-2C-B when exposed to heat is unavailable and the potential for pyrolytic degradation and formation of unknown substances available for inhalation prompted an investigation using a simulated 'meth pipe' scenario. Twelve products following pyrolysis of bk-2C-B were detected and verified by organic synthesis of the corresponding standards. In addition, 2-amino-1-(4-iodo-2,5-dimethoxyphenyl)ethanone hydrochloride (bk-2C-I) has been characterized for the first time and subjected to pyrolysis as well. Similar products were formed, which indicated that the replacement of the bromo with the iodo substituent did not affect the pyrolysis pattern under the conditions used. Two additional products were detected in the bk-2C-I pyrolates, namely 1-(2,5-dimethoxyphenyl)-ethanone and 1-iodo-4-ethenyl-5-methoxyphenol. The potential ingestion of pyrolysis products with unknown toxicity adds an element of concern.
... [19] It has been reported that mephedrone can be administered in a number of ways including orally, nasal insufflation, intramuscular injection, intravenous injection, rectal insertion, inhalation, or vaporization. [20,21] Fatalities associated with its use have been reported throughout the literature. [22][23][24][25][26][27] It is well established at this stage that once a compound is placed under legislative control measures, there is a desire by NPS manufacturers to design and launch novel compounds that circumvent existing drugs legislation in order to fill the gap created in the market. ...
... Both the analytical and pharmacological characterization of mephedrone has been well documented in the scientific literature [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] and studies focusing specifically on synthesis related by-products have also been conducted. [38] The cathinone molecular scaffold gives rise to a large range of biologically active compounds. ...
Article
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3-Methoxy-2-(methylamino)-1-(4-methylphenyl)propan-1-one (mexedrone) appeared in 2015 and was advertised by UK Internet retailers as a non-controlled mephedrone derivative (2-(methylamino)-1-(4-methylphenyl)propan-1-one), which was of particular interest to countries who operate generic drugs legislation. This study describes the synthesis and analytical characterization of mexedrone and the differentiation from its isomer, N-methoxymephedrone, which was predicted to be a suitable candidate before the identity of mexedrone was revealed. A full analytical characterization is described using various chromatographic, spectroscopic and mass spectrometric platforms and X-ray crystal structure analysis. The analytical data obtained for a vendor sample were consistent with the synthesized mexedrone reference standard and analytical differentiation between the mexedrone and N-methoxymephedrone positional isomers was achieved. Furthermore, α-chloromethylmephedrone was identified as a by-product during mexedrone synthesis. All three substances were also studied for their uptake and releasing properties at dopamine transporters (DAT), norepinephrine transporters (NET) and serotonin transporters (SERT) using in vitro monoamine transporter assays in rat brain synaptosomes and compared to mephedrone. Mexedrone was a weak non-selective uptake blocker with IC50 values in the low μM range. It was also devoid of releasing activity at DAT and NET but displayed weak releasing activity at SERT (EC50 = 2.5 μM). The isomer N-methoxymephedrone was found to be a weak uptake blocker at DAT, NET and SERT, as well as a fully efficacious substrate-type releasing agent across all three transporters with EC50 values in the low micromolar range. The synthesis by-product α-chloromethylmephedrone was inactive in all assays
... O relatório concluiu que, em muitos países a mefedrona é comercializada como uma alternativa legal ao ecstasy e a cocaína. A conclusão do estudo foi confirmada por outros estudos que relatam efeitos colaterais indesejáveis, tais como envenenamento, danos no sistema nervoso central, demência e mortes associadas a mefedrona (Schifano F, 2011), (Camilleri, Johnston, Brennan, Davis & Caldicott, 2010), (Busardo, 2015), (Vardakou, Pistos & Spiliopoulou, 2011), (Carhart-Harrist, King & Nut, 2011), (Gibbons & Zloh, 2010 Coloquialmente conhecida como Miaow", "4-MMC", "Meow meow", "Meph", "TopCat", etc (Wood, et al., 2017 (Kavanagh, O'Brien, Power & Talbot, 2013). Dependendo da quantidade de mefedrona tem opção de reembalar em quantidades menores (tipicamente 1 g), de modo que as pessoas podem vender para outras. ...
Article
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En los últimos 25 años en Europa, han surgido nuevas drogas sintéticas derivadas de la planta de khat (Catha edulis), denominadas Catinonas, que es un alcaloide muy potente análogo a las anfetaminas. Entre los derivados de la catinona se encuentra la mefedrina (4-metilmetcatinona (4-MMC)), que tiene efectos farmacológicos equivalentes a los reportados por el éxtasis, las anfetaminas o la cocaína. El presente artículo presenta una revisión exhaustiva de la literatura referente a los principales métodos de detección de la 4-MMC conocida como mefedrona, además de presentar las propiedades fisicoquímicas, farmacológicas, toxicológicas y los principales efectos nocivos para la salud. Es de particular interés y preocupación que este medicamento derivado de la efedrina provenga de una planta y se considere legal en algunos países de Europa occidental. Ha sido ampliamente utilizado en los últimos años con fines recreativos en varios países de Europa, América del Norte y la mayoría de los países de América del Sur debido a su facilidad de compra y por ser una nueva alternativa al éxtasis y la cocaína. Los efectos de la 4-MMC están asociados con efectos estimulantes, como aumento de la concentración, estimulación psicomotora, reducción del apetito e insomnio. Estudios recientes han descrito que el uso compulsivo de mefedrona es principalmente un fenómeno juvenil y entre los efectos secundarios más peligrosos se encuentran la adicción intensa, los cambios bruscos de la temperatura corporal y la frecuencia cardíaca, las alucinaciones, la psicosis y la muerte por sobredosis. Con base en lo anterior, es esencial que las revisiones de la literatura se centren en la química, la farmacología, la toxicología y el análisis de riesgos para la mefedrona, para encontrar estrategias para la determinación rápida y mitigar sus efectos adversos en los adictos, así como evitar el consumo.
... Thermolytic degradants of METH and cocaine include potential carcinogens, and other toxins that cause bronchoconstriction, hypotension, and tachycardia (Chen et al., 1994;Sato et al., 2004;Scheidweiler et al., 2003). The synthetic cathinone mephedrone creates degradants that cause lachrymation and respiratory irritation (Kavanagh et al., 2013). Furthermore, METH and cocaine thermolysis create psychoactive degradants including cocaethylene, amphetamine, and ephedrine (Gayton-Ely et al., 2007;Sekine and Nakahara, 1987). ...
... These "bath salts" are synthetic cathinone powders, distributed under trade names such as 'Ivory Wave' , 'White Lightning' and 'Vanilla Sky' , typically taken by inhalation (snorting), ingestion, or intravenous/ intramuscular injection [6,11]. As with tablets, mephedrone is the most commonly abuse in Europe, whereas MDPV and methylone are more prominent in US bath salts [1]. ...
Article
Full-text available
Context: Synthetic cathinones are a new trend in the recreational drug market and the paucity of human toxicological data combined with their widespread abuse generated great concern in the international scientific community. Objective: Inside the Italian National Early Warning System (NEWS), clinical urine specimens were collected from patients (n=202) admitted to the Emergency Departments (April 2011-January 2013) for clinically suspected abuse of any kind of unknown new psychoactive substances, to measure synthetic cathinones demonstrating the consistency and reliability of the employed screening assays as useful tools to detect these drugs, with the ultimate objective to advance patients care and management. Methods: Screening analyses were performed using two specific ELISA assays, targeting Mephedrone/ methcathinone and MDPV (LOD 0.40 and 20.0 ng/ml, respectively). Data were then compared to determinations gained by LC-MS (LOD 5 ng/ml). Results: (i) Mephedrone/methcathinone: 195/202 samples gave values <7 ng/ml by screening ELISA assay and tested negative by LC-MS. Seven specimens showed concentrations >16 ng/ml (above the upper limit of the standard curve) by screening immunoassay, and only 4 of them resulted positive by LC-MS; (ii) MDPV: 162/167 samples gave values ≤ 60 ng/ml by screening ELISA and tested negative by LC-MS. Five samples showed concentration above the upper limit of the standard curve (>850 ng/ml). Among these, 3/5 samples were confirmed positive by LC-MS (2 for butylone and MDPV, 1 for pentedrone and MDPV). Discussion and conclusion: These results emphasize a good overall match between data obtained by the two analytical methods, showing disagreement in few cases concerning positive results; no false negatives were detected by ELISA screening, suggesting the promising usefulness of this reliable tool as first approach in the emergency setting to rapidly detect synthetic cathinones, allowing the clinician to improve differential diagnosis, aiding real-time patient care and management.
... These "bath salts" are synthetic cathinone powders, distributed under trade names such as 'Ivory Wave' , 'White Lightning' and 'Vanilla Sky' , typically taken by inhalation (snorting), ingestion, or intravenous/ intramuscular injection [6,11]. As with tablets, mephedrone is the most commonly abuse in Europe, whereas MDPV and methylone are more prominent in US bath salts [1]. ...
Article
toxicological data combined with their widespread abuse generated great concern in the international scientific community. Objective: Inside the Italian National Early Warning System (NEWS), clinical urine specimens were collected from patients (n=202) admitted to the Emergency Departments (April 2011-January 2013) for clinically suspected abuse of any kind of unknown new psychoactive substances, to measure synthetic cathinones demonstrating the consistency and reliability of the employed screening assays as useful tools to detect these drugs, with the ultimate objective to advance patients care and management. Methods: Screening analyses were performed using two specific ELISA assays, targeting Mephedrone/ methcathinone and MDPV (LOD 0.40 and 20.0 ng/ml, respectively). Data were then compared to determinations gained by LC-MS (LOD 5 ng/ml). Results: (i) Mephedrone/methcathinone: 195/202 samples gave values <7 ng/ml by screening ELISA assay and tested negative by LC-MS. Seven specimens showed concentrations >16 ng/ml (above the upper limit of the standard curve) by screening immunoassay, and only 4 of them resulted positive by LC-MS; (ii) MDPV: 162/167 samples gave values ≤ 60 ng/ml by screening ELISA and tested negative by LC-MS. Five samples showed concentration above the upper limit of the standard curve (>850 ng/ml). Among these, 3/5 samples were confirmed positive by LC-MS (2 for butylone and MDPV, 1 for pentedrone and MDPV). Discussion and conclusion: These results emphasize a good overall match between data obtained by the two analytical methods, showing disagreement in few cases concerning positive results; no false negatives were detected by ELISA screening, suggesting the promising usefulness of this reliable tool as first approach in the emergency setting to rapidly detect synthetic cathinones, allowing the clinician to improve differential diagnosis, aiding real-time patient care and management.
... Thermolytic degradants of METH and cocaine include potential carcinogens, and other toxins that cause bronchoconstriction, hypotension, and tachycardia (Chen et al., 1994;Sato et al., 2004;Scheidweiler et al., 2003). The synthetic cathinone mephedrone creates degradants that cause lachrymation and respiratory irritation (Kavanagh et al., 2013). Furthermore, METH and cocaine thermolysis create psychoactive degradants including cocaethylene, amphetamine, and ephedrine (Gayton-Ely et al., 2007;Sekine and Nakahara, 1987). ...
... [18] Also, cathinone can readily be oxidized in vitro to 1-phenyl-1,2-propanedione. [19] Therefore, it was postulated that 3',4'methylenedioxyphenyl-1,2-propanedione is also a decomposition product of 1. It has been reported that cathinone derivatives are unstable, for example, with varying pH, [20] with applied heat, [18,21,22] and in air. [23] As a result, a limited study was conducted on the stability of 1 hydrochloride under various conditions. ...
Article
Full-text available
Ethylone, a synthetic cathinone with psychoactive properties, is a designer drug which has appeared on the recreational drug market in recent years. Since 2012, illicit shipments of ethylone hydrochloride have been intercepted with increasing frequency at the Canadian border. Analysis has revealed that ethylone hydrochloride exists as two distinct polymorphs. In addition, several minor impurities were detected in some seized exhibits. In this study, the two conformational polymorphs of ethylone hydrochloride have been synthesized and fully characterized by FTIR, FT-Raman, powder XRD, GC-MS, ESI-MS/MS and NMR ((13) C CPMAS, (1) H, (13) C). The two polymorphs can be distinguished by vibrational spectroscopy, solid-state nuclear magnetic resonance spectroscopy and X-ray diffraction. The FTIR data are applied to the identification of both polymorphs of ethylone hydrochloride (mixed with methylone hydrochloride) in a laboratory submission labelled as 'Ocean Snow Ultra'. The data presented in this study will assist forensic scientists in the differentiation of the two ethylone hydrochloride polymorphs. This report, alongside our recent article on the single crystal X-ray structure of a second polymorph of this synthetic cathinone, is the first to confirm polymorphism in ethylone hydrochloride. © 2015 Canada Border Services Agency. Drug Testing and Analysis published by John Wiley & Sons, Ltd.
... Las sales de baño son polvos de catinona sintética distribuidos bajo nombres comerciales tales como "Ivory Wave", "White Lightning" o "Vanilla Sky" y etiquetados como "no apto para el consumo humano" para evitar la legislación vigente sobre drogas ilegales (Davies et al., 2010;Kasick et al., 2012;Winstock et al., 2011). Estos compuestos se suelen inhalar, pero la congestión nasal lleva a muchos usuarios a fumarlas, ingerirlas, usar la vía rectal, o inyectarlas por vía intravenosa o intramuscular (Kavanagh et al., 2013). Dado que las catinonas sintéticas cristalizadas son solubles en agua, las sales de baño se disuelven fácilmente en las bebidas. ...
Article
Full-text available
Synthetic cathinones are a new class of designer drug of the hallucinogenic stimulant type with effects similar to cocaine, methylenedioxymethamphetamine (MDMA) and other amphetamines. The abuse of synthetic cathinones often included in products sold as “bath salts” became fashionable in early 2009, which led to legislative classification across Europe in 2010 and Schedule I drug classification in the USA in 2011. Recent clinical studies indicate that the action mechanism of synthetic cathinone affects the central monoamine systems. In this paper we will review the history of these drugs, their action mechanism, toxicology and legal aspects.
... [9][10][11] Mephedrone pyrolysis has also been reported to yield a range of degradation products. [12] In addition, GC-based heat-induced formation of artifacts or decomposition products may be observed during the analysis of substituted cathinones, which deserves further study. [13][14][15][16][17][18] As part of the authors' ongoing collective research efforts regarding the systematic preparation and forensically relevant characterization of targeted NPS, the present study reports on the formation of a by-product during mephedrone synthesis. ...
Article
4-Methylmethcathinone (2-methylamino-1-(4-methylphenyl)propan-1-one, mephedrone) is a psychoactive substance that has been associated with recreational use worldwide. Analytical data related to mephedrone are abundantly available but the characterization of by-products obtained during organic synthesis remains to be explored. This study presents the identification of a 1,2,3,5-tetramethyl-4-(4-methylphenyl)-1H-imidazol-3-ium salt (TMMPI), which was formed during the synthesis of mephedrone. When diethyl ether was added to the crude reaction product, solid material precipitated from the solution. Analytical characterization of TMMPI employed a range of analytical techniques including chromatographic analysis in combination with various mass spectrometric detection methods, nuclear magnetic resonance spectroscopy, and crystal structure analysis. Additional confirmation was obtained from organic synthesis of the imidazolium by-product. When TMMPI was subjected to analysis by gas chromatography-mass spectrometry (GC-MS), isomerization and degradation into two distinct compounds were observed, which pointed towards thermal instability under GC conditions. A liquid chromatography-mass spectrometry (LC-MS) based investigation into a micro-scale synthesis of mephedrone and three additional analogues revealed that the corresponding TMMPI analogue was formed. Interestingly, storage of mephedrone freebase in a number of organic solvents also gave rise to TMMPI and it appeared that its formation during storage was significantly reduced in the absence of air. The present study aimed to support clandestine forensic investigations by employing analytical strategies that are applicable to manufacturing sites. The imidazolium salts will most likely be found amongst the waste products of any clandestine lab site under investigation rather than with the desired product. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.
... When underivatized bk-2C-B was analyzed on a different GC-MS instrument, the chromatogram showed 2 peaks, namely, 1-(4-bromo-2,5-dimethoxyphenyl)ethanone (largest peak) and bk-2C-B itself which suggested that formation of 2-bromo-1-(4-bromo-2, 5-dimethoxyphenyl)ethanone and the pyrazine dimer may have been catalyzed by active sites in the GC liner of the injection port. Formation of similar pyrazine dimers have previously been reported [19] and a proposed mechanism of pyrazine formation may be found in the supplementary information (supplementary data 3). Derivatization of both the test purchase and the bk-2C-B standard with HFB and TFA confirmed the presence of bk-2C-B as a single peak in the GC chromatogram (Figure 2b ...
Article
2-Amino-1-(4-bromo-2,5-dimethoxyphenyl)ethan-1-one (bk-2C-B) has been recently offered for purchase by a variety of Internet retailers. This substance may be considered a cathinone analogue of the phenethylamine 2-(4-bromo-2,5-dimethoxyphenyl)ethan-1-amine (2C-B) which suggests that it may have psychoactive effects in humans. A test purchase of bk-2C-B was carried out and its identity was confirmed by a range of analytical techniques including nuclear magnetic resonance spectroscopy, gas and liquid chromatography, and high-resolution mass spectrometry. Confirmation was also obtained from the synthesis of bk-2C-B based on the implementation of the Delépine reaction in which the α-brominated intermediate was reacted with hexamethylenetetramine to afford the primary amine. Analysis of underivatized bk-2C-B by gas chromatography–mass spectrometry (GC-MS) showed that there was potential for artificial formation of 1-(4-bromo-2,5-dimethoxyphenyl)ethanone and a pyrazine dimer, these substances were not detected when employing liquid chromatographic analysis. Ion chromatography and X-ray crystallography analysis confirmed that the purchased bk-2C-B consisted of a hydrochloride and hydrobromide salt mixture, which indicated that it might have been prepared by the hexamethylenetetramine route followed by hydrochloric acid hydrolysis of the quaternary ammonium salt. X-ray crystallography also revealed that the purchased (mixed HCl/HBr salt) and synthesized bk-2C-B (HCl salt) exists as polymorphs. Copyright © 2014 John Wiley & Sons, Ltd.
... Bath salts are synthetic cathinone powders distributed under trade names such as 'Ivory Wave', 'White Lightning' and 'Vanilla Sky' and labeled as "not for human consumption" to avoid penalty under the Analogue Enforcement Act (Addiction, 2011, Davies, Wood, 2010, Kasick et al., 2012, Winstock et al., 2011. These compounds are most frequently insufflated (snorted), but nasal agitation leads many users to smoke bath salts, take them orally or rectally, or to inject them intravenously or intramuscularly (Addiction, 2011, Kavanagh et al., 2012. Since crystallized synthetic cathinones are water soluble, bath salts are readily dissolved in beverages and orally ingested (Addiction, 2011). ...
Article
The synthetic cathinones are an emerging class of designer drugs abused for psychostimulant and hallucinogenic effects similar to cocaine, methylenedioxymethamphetamine (MDMA), or other amphetamines. Abuse of synthetic cathinones, frequently included in products sold as 'bath salts', became prevalent in early 2009, leading to legislative classification throughout Europe in 2010 and schedule I classification within the United States in 2011. Recent pre-clinical and clinical studies indicate dysregulation of central monoamine systems are a principal mechanism of synthetic cathinone action and presumably underlie the behavioral effects and abuse liability associated with these drugs. This review provides insight into the development of synthetic cathinones as substances of abuse, current patterns of their abuse, known mechanisms of their action and toxicology, and the benefits and drawbacks of their classification.
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The detection of illicit psychotropic substances in both indoor and outdoor air is a challenging analytical discipline and the data from such investigation may provide intelligence in a variety of fields. Applications of drug monitoring in air include providing data on national and international drug consumption trends, as monitored by organisations such as the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) and the United Nations Office on Drugs and Crime (UNODC). Air monitoring enables mapping of illicit drug manufacturing, dealing or consumption in cities and the identification of emergent compounds including the recent proliferation of new psychoactive substances (NPS). The rapid spread of NPS has changed the global drug market with greater diversity and dynamic spread of such compounds over several nations. This review provides an up to date analysis of key thematic areas within this analytical discipline. The process of how illicit psychotropic substances spread from emission sources to the atmosphere is considered alongside the sampling and analytical procedures involved. Applications of the technique applied globally are reviewed with studies ranging from the analysis of individual dwellings through to major international air monitoring campaigns providing evidence on global drug trends. Finally, we consider thermal breakdown products of illicit psychotropic substances including NPS that are released upon heating, combustion or vaping and related potential for exposure to these compounds in the air.
Chapter
There has been a significant change in the recreational drugs used throughout the world in the last 5–10 years, with increasing availability and use of a wide range of different new psychoactive substances (NPS, sometimes known as “legal highs”) [1, 2]. A popular emerging class of NPS is the synthetic cathinones. In 2013, there were approximately 35,000 drug seizures of NPS reported to the European Union Early Warning System (EU EWS), of which the most common substance category was cathinones (31%). In 2014, the EU EWS was notified of 101 previously unreported NPS (an increase of 25% from 2013), the largest category of these was cathinones (n = 31, 30.7%) [3]. Globally, cathinones was the third largest group of NPS to be reported by substance group (15%) in the same year [4]. Initially the cathinones, particularly mephedrone (4-methylmethcathinone), were sold undisguised by their chemical names, but they are also, like many other NPS, sold over the Internet and in “head shops” as “research chemicals,” “bath salts,” or “plant food,” often with a warning “not for human consumption” or “not tested for hazards” [3]. This marketing is an attempt to circumvent existing local, national, or international medicinal and/or drug laws [1].
Chapter
There has been a significant change in the recreational drugs used throughout the world in the last 5–10 years, with increasing availability and use of a wide range of different new psychoactive substances (NPS, sometimes known as “legal highs”) [1, 2]. A popular emerging class of NPS is the synthetic cathinones. In 2013, there were approximately 35,000 drug seizures of NPS reported to the European Union Early Warning System (EU EWS), of which the most common substance category was cathinones (31 %). In 2014, the EU EWS was notified of 101 previously unreported NPS (an increase of 25 % from 2013), the largest category of these was cathinones (n = 31, 30.7 %) [3]. Globally, cathinones was the third largest group of NPS to be reported by substance group (15 %) in the same year [4]. Initially the cathinones, particularly mephedrone (4-methylmethcathinone), were sold undisguised by their chemical names, but they are also, like many other NPS, sold over the Internet and in “head shops” as “research chemicals,” “bath salts,” or “plant food,” often with a warning “not for human consumption” or “not tested for hazards” [3]. This marketing is an attempt to circumvent existing local, national, or international medicinal and/or drug laws [1].
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This review summarizes the literature to date relating to pyrolysis and heated vapour ingestion of drugs of abuse. In this context, heating is referred to as smoking or pyrolysis, but these are generic descriptors that encompass numerous methods of vapour generation and inhalation. Depending on the amount of drug used, diluents and contaminants present, heating conditions, and the oxidative/reductive environment, many thermal decomposition products can be formed. In addition to the recognized hazard of rapid onset of pharmacological effects of the parent drug, thermal decomposition products may be pharmacologically active as well as acutely/chronically toxic. For example, several published reports have linked heroin smoking to a form of brain encephalopathy and to the development of movement disorders. Early qualitative studies focusing on the thermal decomposition of drugs have evolved into more complex investigations employing mass spectral identification, confirmation, and elucidation of formation mechanism. In most cases, thermal decomposition begins with cleavage of the weakest bond (often C-N) to generate free radicals that then form the most stable sterically favoured products. Several reports of rearrangements at higher temperatures have been identified and hint at an underlying complexity that arises from the variety of smoking methods and conditions. Given that many designer drugs such as synthetic cannabinoids are ingested primarily through smoking, this issue has taken on new importance. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.
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1-(Thien-2-yl)-2-methylaminopropane (methiopropamine, MPA), appeared as a 'legal high' in late 2010. It is structurally similar to methamphetamine, with a thiophene ring replacing the benzene moiety. Methiopropamine reportedly retains the pharmacological properties of amphetamine stimulants, but it does not fall under existing drug laws in the USA and Ireland. The objective of this research was to identify the pyrolysis products formed under conditions that mimic those used by recreational drugs users. Thirteen pyrolysis products were identified and ten were confirmed by comparison to synthesized standards. Methods for synthesizing the standards as well as an alternative method for the synthesis of methiopropamine were developed. The MPA pyrolysis products are formed through N-dealkylation, N-alkylation, N-formylation, β-carbon oxidation, β-carbon oxidation/N-alkylation, amine elimination and carbon-carbon bond cleavage. Two pyrazine isomers also formed. Some of these products have the potential to be psychoactive while others are potentially toxic. Copyright © 2013 John Wiley & Sons, Ltd.
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International anti-doping efforts are harmonized and regulated under the umbrella of the World Anti-Doping Code and the corresponding Prohibited List, issued annually by the World Anti-Doping Agency (WADA). The necessity for a frequent and timely update of the Prohibited List (as the result of a comprehensive consultation process and subsequent consensual agreement by expert panels regarding substances and methods of performance manipulation in sports) is due to the constantly growing market of emerging therapeutics and thus new options for cheating athletes to illicitly enhance performance. In addition, 'tailor-made' substances arguably designed to undermine sports drug testing procedures are considered and the potential of established drugs to represent a doping substance is revisited in light of recently generated information. The purpose of the annual banned substance review is to support doping controls by reporting emerging and advancing methods dedicated to the detection of known and recently outlawed substances. This review surveys new and/or enhanced procedures and techniques of doping analysis together with information relevant to doping controls that has been published in the literature between October 2010 and September 2011.
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Significant changes in British recreational drug use were seen throughout 2009, with the emergence and rapid growth in the availability and use of substituted cathinones or ‘M-Cats’ (most notably mephedrone and methylone), a group of psychoactive drugs not currently controlled under the Misuse of Drugs Act 1971 (HM Government, 1971), with similar effects to ecstasy, cocaine and amphetamines. The reasons for the appearance and appeal of this group of so-called ‘legal highs’ are explored here in relation to availability, purity, legality and convenience. The authors argue that a reduction in the availability (and thus purity) of illegal drugs such as ecstasy and cocaine and resultant disillusionment among users was a key motivation for displacement to substituted cathinones, conveniently and legally purchased online. Finally, we explore policy considerations around the likely criminalisation of substituted cathinones and the challenge of providing rapid yet considered harm reduction responses to emergent drug trends in the face of a minimal scientific evidence base and eager press demonisation.
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Significant changes in British recreational drug use were seen throughout 2009, with the emergence and rapid growth in the availability and use of substituted cathinones or ‘M-Cats’ (most notably mephedrone and methylone), a group of psychoactive drugs not currently controlled under the Misuse of Drugs Act 1971 (HM Government, 1971), with similar effects to ecstasy, cocaine and amphetamines. The reasons for the appearance and appeal of this group of so-called ‘legal highs’ are explored here in relation to availability, purity, legality and convenience. The authors argue that a reduction in the availability (and thus purity) of illegal drugs such as ecstasy and cocaine and resultant disillusionment among users was a key motivation for displacement to substituted cathinones, conveniently and legally purchased online. Finally, we explore policy considerations around the likely criminalisation of substituted cathinones and the challenge of providing rapid yet considered harm reduction responses to emergent drug trends in the face of a minimal scientific evidence base and eager press demonisation.
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The nonmedical use of ‘designer’ cathinone analogs, such as 4-methylmethcathinone (mephedrone) and 3,4-methylenedioxymethcathinone (methylone), is increasing worldwide, yet little information is available regarding the mechanism of action for these drugs. Here, we employed in vitro and in vivo methods to compare neurobiological effects of mephedrone and methylone with those produced by the structurally related compounds, 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine. In vitro release assays using rat brain synaptosomes revealed that mephedrone and methylone are nonselective substrates for plasma membrane monoamine transporters, similar to MDMA in potency and selectivity. In vivo microdialysis in rat nucleus accumbens showed that i.v. administration of 0.3 and 1.0 mg/kg of mephedrone or methylone produces dose-related increases in extracellular dopamine and serotonin (5-HT), with the magnitude of effect on 5-HT being greater. Both methcathinone analogs were weak motor stimulants when compared with methamphetamine. Repeated administrations of mephedrone or methylone (3.0 and 10.0 mg/kg, s.c., 3 doses) caused hyperthermia but no long-term change in cortical or striatal amines, whereas similar treatment with MDMA (2.5 and 7.5 mg/kg, s.c., 3 doses) evoked robust hyperthermia and persistent depletion of cortical and striatal 5-HT. Our data demonstrate that designer methcathinone analogs are substrates for monoamine transporters, with a profile of transmitter-releasing activity comparable to MDMA. Dopaminergic effects of mephedrone and methylone may contribute to their addictive potential, but this hypothesis awaits confirmation. Given the widespread use of mephedrone and methylone, determining the consequences of repeated drug exposure warrants further study.Keywords: dopamine; MDMA; mesolimbic; microdialysis; serotonin (5-HT); transporters
Article
Full-text available
Significant changes in British recreational drug use were seen throughout 2009, with the emergence and rapid growth in the availability and use of substituted cathinones or ‘M-Cats’ (most notably mephedrone and methylone), a group of psychoactive drugs not currently controlled under the Misuse of Drugs Act 1971 (HM Government, 1971), with similar effects to ecstasy, cocaine and amphetamines. The reasons for the appearance and appeal of this group of so-called ‘legal highs’ are explored here in relation to availability, purity, legality and convenience. The authors argue that a reduction in the availability (and thus purity) of illegal drugs such as ecstasy and cocaine and resultant disillusionment among users was a key motivation for displacement to substituted cathinones, conveniently and legally purchased online. Finally, we explore policy considerations around the likely criminalisation of substituted cathinones and the challenge of providing rapid yet considered harm reduction responses to emergent drug trends in the face of a minimal scientific evidence base and eager press demonisation.
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The designer stimulant 4-methylmethcathinone (mephedrone) is among the most popular of the derivatives of the naturally occurring psychostimulant cathinone. Mephedrone has been readily available for legal purchase both online and in some stores and has been promoted by aggressive Web-based marketing. Its abuse in many countries, including the United States, is a serious public health concern. Owing largely to its recent emergence, there are no formal pharmacodynamic or pharmacokinetic studies of mephedrone. Accordingly, the purpose of this study was to evaluate effects of this agent in a rat model. Results revealed that, similar to methylenedioxymethamphetamine, methamphetamine, and methcathinone, repeated mephedrone injections (4× 10 or 25 mg/kg s.c. per injection, 2-h intervals, administered in a pattern used frequently to mimic psychostimulant "binge" treatment) cause a rapid decrease in striatal dopamine (DA) and hippocampal serotonin (5-hydroxytryptamine; 5HT) transporter function. Mephedrone also inhibited both synaptosomal DA and 5HT uptake. Like methylenedioxymethamphetamine, but unlike methamphetamine or methcathinone, repeated mephedrone administrations also caused persistent serotonergic, but not dopaminergic, deficits. However, mephedrone caused DA release from a striatal suspension approaching that of methamphetamine and was self-administered by rodents. A method was developed to assess mephedrone concentrations in rat brain and plasma, and mephedrone levels were determined 1 h after a binge treatment. These data demonstrate that mephedrone has a unique pharmacological profile with both abuse liability and neurotoxic potential.
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In the condensation of two molecules of 2-hydroxy-2'-aminoacetophenone to form a dihydropyrazine the slow, rate-determining step has been shown, by spectral and kinetic means, to be reaction of two molecules of aminoketone to form an aminoalcohol.
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In the condensation of two molecules of 2-hydroxy-2′- aminoacetophenone to form a dihydropyrazine the slow, rate-determining step has been shown, by spectral and kinetic means, to be reaction of two molecules of aminoketone to form an aminoalcohol.
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Stable 8-π-electron 1,4-dialkyl-1,4-dihydropyrazines are readily prepared by reaction of N-benzyldiphenacylamine hydrobromide with primary aliphatic amines provided care is taken to avoid the subsequent rearrangement. The previously postulated intermediacy of 1,4-dibenzyl-1,4-dihydro-2,6-diphenylpyrazine (1a) in the rearrangement to 1,2-dihydropyrazine 2a is demonstrated and the reaction proceeds in 95 ± 2% yield with first-order kinetics. Crossover recombination experiments show 12 ± 6% intermolecular contribution from a radical dissociation-recombination process which is prevented with butanethiol scavenger. Chiral 24 rearranges in the presence of the scavenger with ≥95% stereospecificity and with inversion of the migrating group indicating an 88 ± 6% component of a concerted [1,3] sigmatropic shift with suprafacial allylic utilization.
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Phenyl α-aminoketones have been shown to undergo carbon skeleton rearrangement to unconjugated aminoketones when heated at 200-240°. The probable intermediate is an unconjugated hydroxyimine formed by base removal of an amine hydrogen and migration of an alkyl group. The hydroxyimine can subsequently rearrange by base removal of a hydroxyl proton and migration of the phenyl grouping. An amine hydrogen has been shown to be necessary by the inactivity of tertiary aminoketones. Unconjugated hydroxyketones have been synthesized and converted to the corresponding unconjugated aminoketones by heating with methylamine at 200°. This lends evidence to the proposed hydroxyimine intermediate.
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Use of the stimulant drug mephedrone increased dramatically in 2009, and it is still available in the United Kingdom after being controlled in April 2010. This study aimed to assess mephedrone's acute cognitive and subjective effects. A mixed within- and between-subjects design compared 20 mephedrone users, first while intoxicated (T1) and secondly drug free (T2); and 20 controls twice when drug free (T1 and T2). Participants' own homes. Healthy adults recruited from the community. Subjective effects, episodic and working memory, phonological and semantic fluency, psychomotor speed and executive control at were assessed at T1 and T2. Trait schizotypy, depression, changes in mephedrone use since the ban and attitudes influencing use of a hypothetical new legal high were indexed at T2 only. Compared with controls, mephedrone users had generally impaired prose recall (P = 0.037) and higher scores in schizotypy (P < 0.001) and depression (P = 0.01). Mephedrone acutely primed a marked 'wanting' for the drug (P < 0.001), induced stimulant-like effects, impaired working memory (P < 0.001) and enhanced psychomotor speed (P = 0.024). Impulsivity in mephedrone users correlated with the number of hours in an average (nearly 8 hour) mephedrone session (r = 0.6). Users would be drawn to use a new legal high if it were pure, had no long/short term harms, and was positively rated by friends or on the internet. Mephedrone impairs working memory acutely, induces stimulant-like effects in users and is associated with binge use. Factors that influence users' attitudes to new drugs might help to predict future trends in use of the many new psychoactive substances emerging on the internet.
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We described a first approach to the pharmacological targets of mephedrone (4-methyl-methcathinone) in rats to establish the basis of the mechanism of action of this drug of abuse. We performed in vitro experiments in isolated synaptosomes or tissue membrane preparations from rat cortex or striatum, studying the effect of mephedrone on monoamine uptake and the displacement of several specific radioligands by this drug. In isolated synaptosomes from rat cortex or striatum, mephedrone inhibited the uptake of serotonin (5-HT) with an IC ₅₀ value lower than that of dopamine (DA) uptake (IC ₅₀=0.31±0.08 and 0.97±0.0 5μM, respectively). Moreover, mephedrone displaced competitively both [³H]paroxetine and [³H]WIN35428 binding in a concentration-dependent manner (Ki values of 17.55±0.78μM and 1.53±0.47 μM, respectively), indicating a greater affinity for DA than for 5-HT membrane transporters. The affinity profile of mephedrone for the 5-HT₂ and D₂ receptors was assessed by studying [³H]ketanserin and [³H] raclopride binding in rat membranes. Mephedrone showed a greater affinity for the 5-HT₂ than for the D₂ receptors. These results provide evidence that mephedrone, interacting with 5-HT and DA transporters and receptors must display a similar pattern of other psychoactive drugs such as amphetamine-like compounds.
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During the analysis of "seized samples", suspected of containing 4-methylmethcathinone (mephedrone) and N-ethylcathinone (ethcathinone) additional compounds were observed in the GCMS chromatogram. These compounds were suspected to be the corresponding phenylacetone isomers of mephedrone and ethcathinone respectively. These isomers are referred to as iso-mephedrone and iso-ethcathinone, respectively. The identity of these compounds was verified by synthesising the isomers from known starting materials and comparing them with the compounds found in the seized samples. Analytical data, GCMS, NMR and IR on these compounds are provided. Possible explanations for the presence of these compounds in the seized samples are explored. Contaminated starting material is one suggestion. Rearrangement of the propiophenone based product to the phenylacetone based product is also suggested. The reaction of the α-bromopropiophenone with a primary amine can also lead to the phenylacetone based product. The presence of these isomeric compounds in seized samples could be used to compare different samples and attempt to establish a common origin.
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This study examined the pyrolysis products of d-methamphetamine (d-MA) and the pyrolysis mechanism. A sealed glass tube, in which MA-HCl was placed, was wrapped with pyrolysis-foil and heated at the Curie point of the pyrolysis-foil. The pyrolysis products of MA were detected by gas chromatography-mass spectrometry and liquid chromatography-electrospray ionization-mass spectrometry. MA-d(3)-HCl, in which all the hydrogen atoms of N-methyl group of MA were substituted with deuterium atoms, was pyrolyzed to investigate the transformation of a methyl group of MA. Amphetamine (AM) and dimethylamphetamine (DMA) were produced via demethylation and methylation reactions, respectively, at temperatures above 315 degrees C. The demethylation and methylation reactions were the major pyrolysis processes at temperatures below 358 degrees C. At temperatures above 315 degrees C, the reaction of DMA with a methyl group eliminated from the methylamino group of MA resulted in the formation of benzylethyltrimethylammonium (BEMA). This transformation reveals that demethylation and methylation reactions occur in the form of a methyl cation. The thermal degradation of BEMA, the abstraction of a proton at the beta-position and the elimination of a trimethylamine, produced allylbenzene, cis-beta-methylstyrene, and trans-beta-methylstyrene at temperatures above 315 degrees C. At temperatures above 445 degrees C, the optical isomers, or l-isomers of AM, MA, and DMA, were produced as pyrolysis products.
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A 36-year old man, having injured himself severely by smashing windows in a rage of fury, was arrested by the police. He died despite resuscitation attempts. The forensic autopsy showed many superficial skin lacerations, bruises and minor brain swelling, but there was no definitive cause of death. Toxicological analysis showed a high concentration of mephedrone in femoral blood (5.1mg/L) and traces of cocaine, MDMA and oxazepam. The remaining dose of mephedrone in the stomach contents was estimated at 113 mg. Tablets that were found in the house of the deceased also contained mephedrone. We attribute this man's death to a fatal oral intake of mephedrone, which probably led to a state of excited delirium. This was aggravated by blood loss from multiple wounds.
Article
Pyrolysis-GC/MS system with on-line micro-furnace was used to make rapid evaluation of ω-chloroacetophenone (CN) decomposition under inert thermal atmospheres. The volatile products evolved during pyrolysis were analyzed by thermal gravimetric analysis (TGA) and Py-GC/MS to obtain specific thermogram and pyrogram. Thermal gravimetric analysis results showed that CN undergoes sublimation at 167°C prior to its decomposition at 229°C. Totally 45 degradation products were identified based on mass spectral library matching with the aid of correlation of the values of boiling point (bp) and retention time. A large number of mono-aromatics and polycyclic aromatic hydrocarbons were observed beyond 600°C. In addition to the aromatic hydrocarbons, oxygenated compounds were also observed during the pyrolysis process. The pyrolysis mechanism was proposed based on the determined pyrolysates and their relative abundance with temperature. The investigation results can provide significant information for understanding the thermal behavior of CN and evaluation of the potential influence of the pyrolysates to living being and the environment.
Article
There is evidence of increasing use of the synthetic cathinone mephedrone (4-methylmethcathinone), particularly amongst clubbers. However, there have only two single case reports of mephedrone toxicity. The aim of this study is to report the pattern of clinical toxicity seen with mephedrone use. We describe 15 patients who presented to our Emergency Department following self-reported mephedrone use. Significant clinical features seen included agitation in 53.3%, tachycardia in 40%, systolic hypertension in 20% and seizures in 20%. Twenty per cent required treatment with benzodiazepines, predominantly for management of agitation. All patients were discharged with no sequelae. Previous user reports have suggested that mephedrone use is associated with cool/blue peripheries; this was not seen in any of the patients in our series. The pattern of toxicity seen with mephedrone in this series is similar to that seen with 1-benzylpiperazine which has recently been classified under UK and EU misuse of drugs legislation. On the basis of this, together with a recent confirmed mephedrone related death in Sweden, we feel that appropriate assessments should be undertaken to determine the legal status of mephedrone.
Article
An accidental death caused by the combined use of a new designer drug, 4-methylmethcathinone (mephedrone), and heroin is reported. A 22-year-old Caucasian male was found unresponsive in his living quarters and was transported to the hospital where he died. During autopsy, needle marks were found along the decedent's lower legs and ankles. Investigators discovered the decedent and his roommate had been using "Black Tar" heroin and mephedrone. Routine toxicological analysis detected morphine in the decedent's blood at 0.06 mg/L. Additionally, 6-acetylmorphine, morphine, codeine, and doxylamine were detected in his urine. A designer drug screen, employing a basic liquid-liquid extraction followed by pentafluropropionic anhydride derivatization, was used to isolate mephedrone from both blood and urine specimens. The derivatized extracts were analyzed by gas chromatography- mass spectrometry (GC-MS) operating in full-scan mode. Quantitative analysis of mephedrone was performed by GC-MS operating in selective ion monitoring mode using methamphetamine-d(14) as an internal standard. Mephedrone was confirmed in the decedent's blood and urine at 0.50 and 198 mg/L, respectively. The physiological and pharmacological effects of mephedrone and any associated toxicity have not been reported. However, because of its structural similarities with methcathinone and the high concentration in the decedent's blood, the overall contribution of mephedrone to the death could not be minimized. Therefore, the medical examiner reported the cause of death as multiple-drug toxicity and the manner of death as accidental.
Article
47 patients with spongiform leucoencephalopathy but no other consistent abnormalities, except brown pigmentation of the alveolar macrophages in the lungs, are described. 11 patients have died. Epidemiological studies indicate at the cause of the illness the inhalatory use of poisoned heroin vapours (pyrolysate). The heroin is primarily sold on the black market in Amsterdam. The Netherlands. Over 170 suspect heroin samples were collected for analysis of the possible poisonous factor. Although suspect, none of the samples could be unambiguously related to the observed illness. Chemical, toxicological, and histopathological investigations have not so far revealed the nature of the poisonous factor, but several neurotoxic agents that are known to cause comparable leucoencephalopathies have been ruled out. This appears to be the first manifestation of the poisonous potential of the unknown causative factor.
Article
The pulmonary effects of the cocaine pyrolysis product, methylecgonidine (MEG; anhydroecgonine methyl ester), were assessed in guinea pigs. Specific airway conductance (SGaw), which decreases during bronchoconstriction, was measured in guinea pigs exposed to atmospheres containing a condensation aerosol of MEG free base (13 +/- 1 mg/liter of air), nebulized MEG fumarate (3 and 12% in phosphate buffered saline) or nebulized acetylcholine chloride (0.2 and 0.4% in phosphate buffered saline). A decrease in SGaw to 24.0 +/- 4.2% (mean +/- 2 S.E.M.) of baseline levels was observed in guinea pigs breathing MEG free base. A decrease to 28.4 +/- 4.5% of baseline was observed following administration of 0.4% acetylcholine. No change in SGaw was measured in guinea pigs exposed to 3% MEG fumarate but SGaw was reduced to 69.3 +/- 5.3% of baseline after exposure to 12% MEG fumarate. MEG free base poses an alkaline challenge to the lung, 3% MEG fumarate is neutral (pH approximately 7.4) and 12% MEG fumarate is acidic (pH approximately 4.3); thus, MEG free-base and 12% MEG fumarate might provoke a reflex bronchoconstriction due to direct pulmonary irritant effects. These results suggest that MEG free base produced during crack pyrolysis may play a role in bronchoconstriction observed in crack smokers.
Emergency department visits after use of a drug sold as "bath salts
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Emergency department visits after use of a drug sold as " bath salts " -Michigan
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Emergency department visits after use of a drug sold as “bath salts”-Michigan, November 13, 2010-March 31
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